Oral anticancer agents as generators of relevant pharmacokinetic interactions.

INTRODUCTION: The goal of this paper is to review the impact of marketed oral anticancer agents on the pharmacokinetics of co-administered medications in humans focusing on clinically relevant interactions. METHODS: We identified the oral anticancer agents marketed in the United States and in Europe as December 31, 2021. Based on prescription information and literature, we selected the agents that were moderate/strong inducers or inhibitors of pharmacokinetic human molecular determinants of pharmacological interest (enzymes, drug transporters) highlighting on clinically meaningful interactions (i.e., at least a 2-fold variation in exposure of the comedication, excepting 1.5 for digoxin). RESULTS: As December 31, 2021, 125 marketed oral anticancer agents were identified. Based on a≥2-fold exposure change (≥ 1.5 for digoxin), 24 oral anticancer agents commercialised in the European Union and the United States are susceptible to generate clinically meaningful pharmacokinetic interactions with comedications. All are recent agents and most of them (19/24) are indicated in the treatment of solid tumours. In all, 32 interactions with human molecular kinetic determinants were found for the 24 agents. Most of the pharmacokinetic interactions (26/32) are driven through cytochrome P450 (CYP) inhibition or induction, CYP3A4 being the major contributor (15). CONCLUSION: 24 anticancer agents (20% of the oral market) have the potential to significantly interact with co-administered drugs. These potential pharmacokinetic interactions are likely to occur in the ambulatory setting in a polymedicated and aged population, needing to reinforce the vigilance of community pharmacists and health care providers (particularly in thoracic oncology and genitourinary cancer) with these sometimes rarely prescribed agents.

Clinical Pharmacokinetics and Pharmacodynamics of Dasatinib.

Dasatinib is an oral, once-daily tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. Dasatinib is rapidly absorbed, with the time for maximal serum concentration varying between 0.25 and 1.5 h. Oral absorption is not affected by food. The absolute bioavailability of dasatinib in humans is unknown due to the lack of an intravenous formulation preventing calculation of the reference exposure. Dasatinib is eliminated through cytochrome P450 (CYP) 3A4-mediated metabolism, with a terminal half-life of 3-4 h. Based on total radioactivity, only 20% of the oral dose (100 mg) is recovered unchanged in faeces (19%, including potential non-absorption) and urine (1%) after 168 h. Dasatinib pharmacokinetics are not influenced by age (children, and adults up to 86 years of age), race and renal insufficiency. Dasatinib absorption is decreased by pH-modifying agents (antacids, H2-receptor blockers, proton pump inhibitors), and dasatinib is also subject to drug interactions with CYP3A4 inducers or inhibitors.

The role of therapeutic drug monitoring in the management of safety of anticancer agents: a focus on 3 cytotoxics.

Introduction: Therapeutic drug monitoring in oncology is used to prevent major toxicities of selected anticancer agents due to overexposure by individualizing the dose based on a pharmacokinetic target. Areas covered: Numerous studies relating a relation between pharmacokinetic variability and toxicity have been reported since the eighties but very few have been implemented in clinical practice due to a lack of validation and harmonization, logistical constraints and reluctance from oncologists. Following recent recommendations, this paper highlights the current-validated applications of pharmacokinetic monitoring in oncology focusing on the safety of anticancer therapies. Expert opinion: Paradoxically given the oldness of the agents, guidelines of dose adjustment have been recently available for intravenous busulfan, 5-fluorouracil, and high-dose methotrexate. Interestingly, besides the enhancement of tolerability, it applies to potential curative clinical situations. In an era of personalized oncology that integrates complex molecular factors in the treatment of cancer, education is needed for oncologists to show the benefits of this valuable (even old) resource for the safety of patients. Therapeutic drug monitoring for busulfan, 5-fluorouracil and methotrexate will still hold in the future unless more active agents are available in the concerned indications.

[Funding of anticancer drugs in France]. / Modalités de financement des médicaments anticancéreux en France.

This short review presents the modalities of funding of anticancer agents administrated in hospitals in France.

Knowledge, behaviors and practices of community and hospital pharmacists towards biosimilar medicines: Results of a French web-based survey.

This study's aims were: 1) to extract a comprehensive overview of the knowledge, experience and opinions of both community pharmacists and hospital pharmacists regarding biosimilar medicines in France; and 2) to identify the perceived problems and solutions to promoting their prescription. A 2015 web-based survey was conducted by the Observatoire des Médicaments, des Dispositifs Médicaux et de l'Innovation Thérapeutique of Alsace. A total of 802 pharmacists responded to the survey. Many (536, 66.8%, [95% confidence interval (CI) 63.6-70.1]) indicated that they were not familiar with biosimilars. Half of community pharmacists (95% CI 42.7-57.3) stated that they were not at all informed about biosimilar drugs, compared with 15.7% (95% CI 12.9-18.6) of hospital pharmacists. Almost all respondents (781, 97.4%, [95% CI 96.3-98.5]) had at least one pending question on biosimilars. Most of the questions were related to the manufacturing process, safety, substitution rules and the international non-proprietary name prescription. At the time of the study, 467 pharmacists (58.2%, [95% CI 54.8-61.6]) had already validated a prescription for a biosimilar drug, mainly for filgrastim. These latter were more comfortable in explaining the benefit of biosimilar medicines to the patient. Pharmacists were rather favorable to biosimilar drugs, and about 9 of 10 quoted healthcare cost savings as incentives to their prescription. However, many did not agree with allowing biosimilar substitution. "Patients' wishes to be treated with the originator" and "indication extrapolation" were the two main constraints identified. The survey highlighted the need to provide French pharmacists with accurate and comprehensive information regarding biosimilar medicines.

Rheumatologists' Perceptions of Biosimilar Medicines Prescription: Findings from a French Web-Based Survey.

BACKGROUND: Healthcare cost savings are closely linked to prescribers' confidence in and acceptance of the prescription of biosimilar drugs. OBJECTIVES: The aim of this study was to assess the knowledge, experience and opinions of hospital-based and office-based French rheumatologists with regard to biosimilar medicines and to identify the barriers to and possible options to promote their prescription. METHODS: A web-based, self-administered survey was conducted among French rheumatologists from June 8 to August 2, 2015. RESULTS: A total of 116 rheumatologists responded to the survey. Many reported having little knowledge and a lack of available information about biosimilar drugs, especially office-based rheumatologists. 98.3% of the respondents had at least one question about biosimilars, and seven in ten raised issues regarding substitution, iatrogenic effects or cost savings that might be achievable. Only eight rheumatologists had already prescribed a biosimilar drug. The most common barriers reported were indication extrapolation and a lack of data about tolerability. Nine out of ten physicians thought that starting a treatment with a biosimilar drug in biologic treatment-naïve patients was possible. The rheumatologists' opinions were rather favorable towards the implementation of biosimilars, but a majority expressed a negative opinion about substitution by the pharmacist. CONCLUSIONS: Our survey gave a better appreciation of the concerns associated with biosimilar prescriptions. Targeted communication initiatives, deeper experience and availability of new clinical data may help to address the outstanding questions and should overcome the misunderstandings surrounding biosimilar drugs among rheumatologists.

Off-label use of targeted therapies in oncology.

Off-label use is defined by the prescription of a marketed drug outside the conditions described in the summary of product characteristics. In oncology, off-label prescribing of targeted therapies may occur in patients with other tumor types expressing the same target. Agents associated to phenotypic approaches such as therapies against the tumoral vasculature (anti-angiogenic drugs) and new immunotherapies (checkpoint inhibitors) also carry the potential of alternative indications or combinations. Off-label use of targeted therapies is little documented and appears to be in the same range than that regarding older drugs with wide variations among agents. When compared with older agents, off-label use of targeted therapies is probably more rational through tumoral genotyping but is faced with a limited clinical support, reimbursement challenges related to the very high pricing and the cost of genotyping or molecular profiling, when applicable.

[Biosimilar drugs in oncology]. / Médicaments biosimilaires en oncologie.

Biosimilar drugs are biologic drugs clinically similar to the reference products. They correspond to a generic approach applied to biologic agents. Biosimilars are aimed to provide cheaper drugs by enhancing the concurrency. The approval of biosimilars is abbreviated when compared to that of the reference biologics but includes clinical trials (distinguishing them from the generics). Current available biosimilars in oncology are filgrastim and epoietin alpha. In the next future, will be launched rituximab and trastuzumab. In France, the development of biosimilars is faced with many hurdles that necessitates a better information of physicians and a greater price discount in the out-patient setting. More globally, harmonisation of recommendations particularly concerning extrapolation of indications and nomenclature are needed for a better acceptance.

Impact of clinical pharmacy services in a hematology/oncology inpatient setting.

BACKGROUND/AIM: Clinical pharmacists are contributing to safe medication use by providing comprehensive management to patients and medical staff. However, little is known regarding their impact in oncology. The aim of this study was to document and evaluate the role of clinical pharmacy services in a hematology/oncology department. PATIENTS AND METHODS: A prospective, descriptive, observational study was carried out from May 2012 to May 2013. Medication reviews concerning hospitalized adult cancer patients were performed twice a week. Medication problems, pharmaceutical interventions and acceptance rate by the oncologists were recorded by a clinical pharmacist. RESULTS: A total of 4,393 prescriptions (including chemotherapy and support) of 489 adult cancer patients (mean age=63 years) were analyzed. The pharmacist identified 552 drug-related problems (12.6% of the prescriptions) primarily related to anti-infective agents (59.5%). Medication problems included inappropriate medications (20.6%), untreated indications (14.8%), inappropriate administrations (14.1%), underdosing (11.7%), drug-drug interactions (14.3%), lack of monitoring (9.6%), overdosing (8.9%), administration omissions (3.5%) and side-effects (2.5%). Interventions (n=552) led to treatment discontinuation (26.2%), drug dosing adjustments (21.5%), drug additions (16.9%), alternate routes of administration (11.7%), replacement of a drug by another one (10.7%), therapeutic drug monitoring (10.3%) and optimizing administration (2.6%). Most (96%) of the interventions were accepted and implemented by the medical staff. CONCLUSION: The integration of clinical pharmacy services resulted in drug-specific interventions in 12.6 % of the prescriptions of hospitalized adult patients with cancer. Medication problems mostly concerned anti-infective agents. The intervention acceptance rate by oncologists was high. The outcome of care in the hematology/oncology inpatient setting remains to be measured.

[Mecanisms of pharmacokinetic interactions involving oral anticancer agents]. / Mécanismes des interactions pharmacocinétiques impliquant les agents anticancéreux oraux.

Oral anticancer agents and particularly kinase inhibitors are subject to pharmacokinetic drug interactions in relation to absorption and elimination phases. Interacting factors are food, fruit juices, cigarette smoke, acid-reducing agents and inducers/inhibitors. Some anticancer agents are inducers and/or inhibitors and can also perpetrate drug interactions. This review emphasizes the mechanisms of pharmacokinetic drug interactions involving oral anticancer agents.

Fatal stimulation of acute myeloid leukemia blasts by pegfilgrastim.

UNLABELLED: We herein report the case of a male patient with acute myeloid leukemia with fatal outcome attributable to pharmacokinetics of pegfilgrastim. CASE REPORT: An unexplained blast proliferation in a patient with acute myeloid leukemia following cytotoxic induction chemotherapy was investigated in depth. Myeloblast hyperstimulation was likely related to pegfilgrastim, the long half-life of which extended the duration of side-effects, resulting in massive and rapidly fatal leukemia cell proliferation. CONCLUSION: Pegfilgrastim can cause unexpected deleterious effects in acute myeloid leukemia. We, thus, recommend administering drugs with a shorter half-life, such as filgrastim or lenograstim, to reduce infection incidence in patients receiving myelosuppressive chemotherapy associated with a clinically significant incidence of febrile neutropenia.

Therapeutic drug monitoring in cancer--are we missing a trick?

Therapeutic drug monitoring (TDM) can be defined as the measurement of drug in biological samples to individualise treatment by adapting drug dose to improve efficacy and/or reduce toxicity. The cytotoxic drugs are characterised by steep dose-response relationships and narrow therapeutic windows. Inter-individual pharmacokinetic (PK) variability is often substantial. There are, however, a multitude of reasons why TDM has never been fully implemented in daily oncology practice. These include difficulties in establishing appropriate concentration target, common use of combination chemotherapies and the paucity of published data from pharmacological trials. The situation is different with targeted therapies. The large interindividual PK variability is influenced by the pharmacogenetic background of the patient (e.g. cytochrome P450 and ABC transporters polymorphisms), patient characteristics such as adherence to treatment and environmental factors (drug-drug interactions). Retrospective studies have shown that targeted drug exposure correlates with treatment response in various cancers. Evidence for imatinib currently exists, others are emerging for compounds including nilotinib, dasatinib, erlotinib, sunitinib, sorafenib and mammalian target of rapamycin (mTOR) inhibitors. Applications for TDM during oral targeted therapies may best be reserved for particular situations including lack of therapeutic response, severe or unexpected toxicities, anticipated drug-drug interactions and concerns over adherence treatment. There are still few data with monoclonal antibodies (mAbs) in favour of TDM approaches, even if data showed encouraging results with rituximab and cetuximab. TDM of mAbs is not yet supported by scientific evidence. Considerable effort should be made for targeted therapies to better define concentration-effect relationships and to perform comparative randomised trials of classic dosing versus pharmacokinetically-guided adaptive dosing.

Review of therapeutic drug monitoring of anticancer drugs part 1--cytotoxics.

Most anticancer drugs are characterised by a steep dose-response relationship and narrow therapeutic window. Inter-individual pharmacokinetic (PK) variability is often substantial. The most relevant PK parameter for cytotoxic drugs is the area under the plasma concentration versus time curve (AUC). Thus it is somewhat surprising that therapeutic drug monitoring (TDM) is still uncommon for the majority of agents. Goals of the review were to assess the rationale for more widely used TDM of cytotoxics in oncology. There are several reasons why TDM has never been fully implemented into daily oncology practice. These include difficulties in establishing appropriate concentration target ranges, common use of combination chemotherapies for many tumour types, analytical challenges with prodrugs, intracellular compounds, the paucity of published data from pharmacological trials and 'Day1 = Day21' administration schedules. There are some specific situations for which these limitations are overcome, including high dose methotrexate, 5-fluorouracil infusion, mitotane and some high dose chemotherapy regimens. TDM in paediatric oncology represents an important challenge. Established TDM approaches includes the widely used anticancer agents carboplatin, busulfan and methotrexate, with 13-cis-retinoic acid also recently of interest. Considerable effort should be made to better define concentration-effect relationships and to utilise tools such as population PK/PD models and comparative randomised trials of classic dosing versus pharmacokinetically guided adaptive dosing. There is an important heterogeneity among clinical practices and a strong need to promote TDM guidelines among the oncological community.